Multi-layered orally disintegrating tablet and the manufacture thereof

ABSTRACT

The present invention features a tablet containing a first layer and a second layer, wherein: (i) the first layer includes a pharmaceutically active agent and the composition of the first layer is different from the composition of the second layer; (ii) the tablet has a density less than about 0.8 g/cc; and (iii) the tablet disintegrates in the mouth when placed on the tongue in less than about 30 seconds.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional application which claims the benefits of U.S.patent application Ser. No. 13/052,316, filed Mar. 21, 2011, U.S. patentapplication Ser. No. 12/887,552, filed Sep. 22, 2010, U.S. patentapplication Ser. No. 12/887,544, filed Sep. 22, 2010 (now U.S. Pat. No.8,871,263), U.S. Provisional Application Ser. No. 61/358,167, filed Jun.24, 2010, U.S. Provisional Application Ser. No. 61/314,629, filed Mar.17, 2010, U.S. Provisional Application Ser. No. 61/255,582, filed Oct.28, 2009, U.S. Provisional Application Ser. No. 61/245,315, filed Sep.24, 2009. The complete disclosures of the aforementioned related U.S.patent applications are hereby incorporated herein by reference for allpurposes.

BACKGROUND OF THE INVENTION

Pharmaceuticals intended for oral administration are typically providedin tablet form. Tablets are swallowed whole, chewed in the mouth, ordisintegrated in the oral cavity. Soft tablets that either are chewed ordissolve in the mouth are often employed in the administration ofpharmaceuticals where it is impractical to provide a tablet forswallowing whole. With chewable tablets, the act of chewing helps tobreak up the tablet particles as the tablet disintegrates and mayincrease the rate of absorption by the digestive tract. Soft tablets arealso advantageous where it is desirable to make a pharmaceuticallyactive agent available topically in the mouth or throat for both localeffects and/or systemic absorption. Soft tablets are also utilized toimprove drug administration in pediatric and geriatric patients. Softtablets designed to disintegrate in the mouth prior to swallowing areparticularly useful for improving compliance of pediatric patients.

Generally, soft tablets are made by compaction of a blend of powderedingredients and typically include a pharmaceutically active agent,flavoring, and/or binders. The powder blend is typically fed into thecavity of a die of a tablet press and a tablet is formed by applyingpressure. Hardness of the resulting tablet is a direct function of thecompaction pressure employed and the compatibility of the ingredients inthe formulation. A softer tablet, having an easier bite-through, may beprepared by employing reduced compaction pressures. The resulting tabletis softer, but also more fragile, brittle, and easily chipped anddisadvantageously can involve complex and costly processing steps.Examples of soft tablets designed to disintegrate in the mouth withoutchewing are disclosed in U.S. Pat. Nos. 5,464,632, 5,223,264, 5,178,878,6,589,554, and 6,224,905.

There is a need for aesthetically pleasing chewable and orallydisintegrating tablets that utilizes compression-based tabletingmachines typically used to produce high density, hard swallowabletablets. When used at low compression forces, these machines typicallyproduce highly friable tablets, which are not sufficiently stable duringpackaging, shipping, and storage. The present invention relates to thediscovery of a process for making tablets, such as chewable or orallydisintegrating tablets, using radiofrequency energy (“RF energy”) thatcan utilize high speed tableting machines.

SUMMARY OF THE INVENTION

In one aspect, the present invention features a process for making atablet by compacting a powder blend in a die platen to form a tabletshape, wherein the powder blend includes a pharmaceutically active agentand a meltable binder, and applying radiofrequency energy to the tabletshape for a sufficient period of time to soften or melt the binderwithin the tablet shape to form the tablet. In one embodiment, theresulting tablet is an orally disintegrating tablet (“ODT”).

In one aspect, the present invention features a tablet containing afirst layer and a second layer, wherein: (i) the first layer includes apharmaceutically active agent and the composition of the first layer isdifferent from the composition of the second layer; (ii) the tablet hasa density less than about 0.8 g/cc; and (iii) the tablet disintegratesin the mouth when placed on the tongue in less than about 30 seconds.

In another aspect, the present invention features a process for making atablet comprising a first layer and a second layer, the method includingthe steps of: (i) adding a first powder blend to a die platen, whereinthe first powder blend includes a pharmaceutically active agent and abinder; (ii) adding a second powder blend to the die platen, wherein thesecond powder blend includes a binder and wherein the composition of thesecond powder blend is different from the composition of the firstpowder blend; (iii) compacting a first powder blend and a second powderblend in the die platen to form a tablet shape; and (iv) applying energyto the tablet shape for a sufficient period of time to activate thebinders within the tablet shape to fuse the tablet shape into the tabletsuch that the tablet has a density less than about 0.8 g/cc and thetablet disintegrates in the mouth when placed on the tongue in less thanabout 30 seconds.

Other features and advantages of the present invention will be apparentfrom the detailed description of the invention and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-F are cross-section, side views of an embodiment of theinvention showing the manufacture of tablet 4 a from powder blend 4within die platen 2.

FIGS. 2A-H are cross-section, side views of an embodiment of theinvention showing the manufacture of a bilayer tablet 12 from powderblends 10 and 11 within die platen 2.

FIGS. 3A-G are cross-section, side views of an embodiment of theinvention showing the manufacture of tablet 40 containing preformedinserts 30 and 31 from powder blend 20 within die platen 2.

FIGS. 4A and 4B are a perspective view of a rotary indexing machine 195.

FIGS. 5A and 5B are top views of the rotary indexing machine 195 in thedwell position.

FIGS. 6A and 6B are section views of the lower forming tool assembly 110in the start position of the manufacturing cycle.

FIG. 7 is a section view through the RF station rotary indexing machine195 prior to compacting powder blend 101.

FIG. 8 is a section view through the RF station rotary indexing machine195 prior showing the manufacture of tablets 101 a.

FIG. 9 is a section view through tablet ejection station 160 beforetablets 101 a have been ejected.

FIG. 10 is a section view through tablet ejection station 160 aftertablets 101 a have been ejected into blister 190.

FIGS. 11A-D are cross sections of alternate embodiments of forming toolsand the die platen.

FIGS. 12A-D are cross sections of alternate embodiments of forming toolsand the die platen.

FIG. 13A is a cross section of forming tools having a wave-shapedsurface.

FIG. 13B is a perspective view of forming tools having a wave-shapedsurface.

FIG. 14 is a cross section of forming tools having protrusions at thesurface.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can, based upon thedescription herein, utilize the present invention to its fullest extent.The following specific embodiments can be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention belongs. Also, all publications, patentapplications, patents, and other references mentioned herein areincorporated by reference. As used herein, all percentages are by weightunless otherwise specified.

As discussed above, in one aspect, the present invention features aprocess for making a tablet by compacting a powder blend in a die platento form a tablet shape, wherein the powder blend includes apharmaceutically active agent and a meltable binder, and applyingradiofrequency energy to the tablet shape for a sufficient period oftime to soften or melt the binder within the tablet shape to form thetablet.

Powder Blend

As discussed above, the tablet is manufactured by compacting a powderblend containing a pharmaceutically active agent (as discussed herein),a binder (as discussed herein), and optionally apharmaceutically-acceptable carrier. Examples of binders include but arenot limited to meltable binders and water-activating binding materials.The carrier contains one or more suitable excipients for the formulationof tablets. Examples of suitable excipients include, but are not limitedto, fillers, adsorbents, disintegrants, lubricants, glidants,sweeteners, superdisintegrants, flavor and aroma agents, antioxidants,preservatives, texture enhancers, and mixtures thereof. One or more ofthe above ingredients may be present on the same particle of the powderblend.

Suitable fillers include, but are not limited to, carbohydrates (asdiscussed herein) and water insoluble plastically deforming materials(e.g., microcrystalline cellulose or other cellulosic derivatives), andmixtures thereof.

Suitable adsorbents include, but are not limited to, water-insolubleadsorbents such as dicalcium phosphate, tricalcium phosphate, silicifiedmicrocrystalline cellulose (e.g., such as distributed under the PROSOLVbrand (PenWest Pharmaceuticals, Patterson, N.Y.)), magnesiumaluminometasilicate (e.g., such as distributed under the NEUSILIN brand(Fuji Chemical Industries (USA) Inc., Robbinsville, N.J.)), clays,silicas, bentonite, zeolites, magnesium silicates, hydrotalcite, veegum,and mixtures thereof.

Suitable disintegrants include, but are not limited to, sodium starchglycolate, cross-linked polyvinylpyrrolidone, cross-linkedcarboxymethylcellulose, starches, microcrystalline cellulose, andmixtures thereof.

Suitable lubricants include, but are not limited to, long chain fattyacids and their salts, such as magnesium stearate and stearic acid,talc, glycerides waxes, and mixtures thereof.

Suitable glidants include, but are not limited to, colloidal silicondioxide.

Examples of sweeteners include, but are not limited to, synthetic ornatural sugars; artificial sweeteners such as saccharin, sodiumsaccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose,dihydrochalcone, alitame, miraculin, monellin, and stevside; sugaralcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol, andxylitol; sugars extracted from sugar cane and sugar beet (sucrose),dextrose (also called glucose), fructose (also called laevulose), andlactose (also called milk sugar); isomalt, salts thereof, and mixturesthereof.

Examples of superdisintegrants include, but are not limited to,croscarmellose sodium, sodium starch glycolate and cross-linked povidone(crospovidone). In one embodiment the tablet contains up to about 5% byweight of such superdisintegrant.

Examples of flavors and aromatics include, but are not limited to,essential oils including distillations, solvent extractions, or coldexpressions of chopped flowers, leaves, peel or pulped whole fruitcontaining mixtures of alcohols, esters, aldehydes and lactones;essences including either diluted solutions of essential oils, ormixtures of synthetic chemicals blended to match the natural flavor ofthe fruit (e.g., strawberry, raspberry and black currant); artificialand natural flavors of brews and liquors, e.g., cognac, whisky, rum,gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint;fruit juices including expelled juice from washed, scrubbed fruits suchas lemon, orange, and lime; spear mint, pepper mint, wintergreen,cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseedsnuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts),almonds, raisins; and powder, flour, or vegetable material partsincluding tobacco plant parts, e.g., genus Nicotiana, in amounts notcontributing significantly to the level of nicotine, and ginger.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.

Examples of preservatives include, but are not limited to, citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid, and mixtures thereof.

Examples of texture enhancers include, but are not limited to, pectin,polyethylene oxide, and carrageenan, and mixtures thereof. In oneembodiment, texture enhancers are used at levels of from about 0.1% toabout 10% percent by weight.

In one embodiment of the invention, the powder blend has an averageparticle size of less than 500 microns, such as from about 50 microns toabout 500 microns, such as from about 50 microns and 300 microns.Particles in this size range are particularly useful for directcompacting processes.

In one embodiment, the powder blend/tablet is substantially free ofsuperdisintegrants. As used herein, what is meant by “substantiallyfree” is less than 5%, such as less than 1%, such as less than 0.1%,such as completely free (e.g., 0%). Examples of superdisintegrantsinclude, but are not limited to, starch glycolate, cross-linkedpolyvinylpyrrolidone, and cross-linked carboxymethylcellulose.

In one embodiment, powder blend/tablet is substantially free of directlycompressible water insoluble fillers. Water insoluble fillers includebut are not limited to microcrystalline cellulose, directly compressiblemicrocrystalline cellulose, celluloses, water insoluble celluloses,starch, cornstarch and modified starches. As described in thisembodiment, substantially free is less than 2 percent, e.g. less than 1percent or none.

Meltable Binder

In one embodiment, the powder blend/tablet of the present inventionincludes at least one meltable binder. In one embodiment, the meltablebinder has a melting point of from about 30° C. to about 140° C., suchas from about 40° C. to about 140° C., such as from about 55° C. toabout 100° C. The softening or melting of the meltable binder(s) resultsin the sintering of the tablet shape through the binding of the softenedor melted binder with the pharmaceutically active agent and/or otheringredients within the compacted powder blend.

In one embodiment, the meltable binder is a RF-meltable binder. What ismeant by an RF-meltable binder is a solid binder that can be softened ormelted upon exposure to radiofrequency (“RF”) energy. The RF-meltablebinder typically is polar and has the capability to re-harden orresolidify upon cooling.

In one embodiment, the RF meltable binder is not a RF-meltable binder.In such embodiment, the powder blend contains an excipient that heatsupon exposure to RF energy (e.g., a polar excipient), such that theresulting heat from is able to soften or melt the meltable binder.Examples of such excipients include, but are not limited to, polarliquids such as water and glycerin; powdered metals and metal salts suchas powdered iron, sodium chloride, aluminum hydroxide, and magnesiumhydroxide; stearic acid; maltodextrin and sodium stearate.

Other examples of meltable binders include amorphous carbohydratepolymers. What is meant by an “amorphous carbohydrate polymer” is amolecule having a plurality of carbohydrate monomers wherein suchmolecule has a crystallinity of less than 20%, such as less than 10%,such as less than 5%. Examples of amorphous carbohydrate polymersinclude, but are not limited to hydrogenated starch hydrosolate,polydextrose, and oligosaccharides. Examples of oligosaccharidesinclude, but are not limited to, fructo-oligosaccharide,galacto-oligosaccharide malto-oligosaccharide, inulin, andisolmalto-oligosaccharide

Examples of suitable meltable binders include: fats such as cocoabutter, hydrogenated vegetable oil such as palm kernel oil, cottonseedoil, sunflower oil, and soybean oil; mono, di, and triglycerides;phospholipids; cetyl alcohol; waxes such as Carnauba wax, spermacetiwax, beeswax, candelilla wax, shellac wax, microcrystalline wax, andparaffin wax; water soluble polymers such as polyethylene glycol,polycaprolactone, GlycoWax-932, lauroyl macrogol-32 glycerides, andstearoyl macrogol-32 glycerides; polyethylene oxides; and sucroseesters.

In one embodiment, the meltable binder is a RF-meltable binder, and theRF-meltable binder is a polyethylene glycol (PEG), such as PEG-4000. Aparticularly preferred RF-meltable binder is PEG having at least 95% byweight of the PEG particles less than 100 microns (as measured byconventional means such as light or laser scattering or sieve analysis)and a molecular weight between 3000 and 8000 Daltons.

The meltable binder(s) may be present at level of about 0.01 percent toabout 70 percent of the powder blend/tablet, such as from about 1percent to about 50 percent, such as from about 10 percent to about 30percent of the powder blend/tablet.

In one embodiment, the average particle size of the binder is less than250 microns, such as less than 100 microns.

Water-Containing Material

In one embodiment, the powder blend/tablet of the present inventionincludes at least one water-containing material. Examples ofwater-containing materials include, but are not limited to, materialswherein the water is chemically bound to the material (e.g., a hydratesalt), materials wherein the water is adsorbed or absorbed to thematerial (e.g., porous material such a silicas and microsponges), andmaterials that have water encapsulated therein (e.g., liquid filledcapsules). Examples of such materials include, but are not limited to:fumed silicas; colloidal silicas such as colloidal silicon dioxide;silicates such as calcium silicate, aluminum silicate, magnesiumaluminum metasilicate (such as NEUSILIN, US-2 from Fuji Chemical Ltd),and magnesium silicate; clays; zeolites; and veegum.

In one embodiment, the powder blend/tablet contains at least onehydrated salt. Examples of hydrated salts include, but are not limitedto, sodium sulfate hydrate, sodium carbonate hydrate, calcium chloridehydrate, sodium hydrogen phosphate hydrate, and mixtures thereof. In oneembodiment, the hydrated salt has molecular weight from about 150 toabout 400 Daltons, such as from about 200 to about 350 Daltons.

In one embodiment, the powder blend/tablet contains at least one liquidfilled capsule. In a further embodiment, the water is released from thecapsule upon rupture, wherein such rupture is caused by the addition ofenergy.

The water-containing material(s) may be present at level of about 0.01percent to about 70 percent of the powder blend/tablet, such as fromabout 1 percent to about 50 percent, such as from about 1 percent toabout 30 percent, such as from about 2 percent to about 10 percent ofthe powder blend/tablet.

Water-Activating Binding Material

In one embodiment, the powder blend/tablet of the present inventionincludes at least one water-activating binding material. What is meantby a water-activating binding material is a material that will activateor hydrate upon contact with water (e.g. released from the watercontaining material upon the addition of the energy) and assist inbinding/fusing the powder blend into a tablet. Examples of suchmaterials include, but are not limited to, hydrolyzed proteins,hydrating polymers and hydrocolloids. Suitable hydrolyzed proteinsinclude, but are not limited to, hydrolyzed collagen. Suitable hydratingpolymers include, but are not limited to starches, modified starches,methylcellulose, hydroxypropylcellulose, and hydroxypropylcellulose.Suitable hydrocolloids include, but are not limited to, gelatin, gellangum, carrageenan, and pectin.

Carbohydrate

In one embodiment, the powder blend contains at least one carbohydrate.The carbohydrate can contribute to the dissolvability and mouth feel ofthe tablet, aid in distributing the meltable binder across a broadersurface area, and diluting and cushioning the pharmaceutically activeagent. In one embodiment, the carbohydrate particles (e.g., sorbitol)act as the binder and are sintered upon heating. Examples ofcarbohydrates include, but are not limited to, water-solublecompressible carbohydrates such as sugars (e.g., dextrose, sucrose,maltose, isomalt, and lactose), starches (e.g., corn starch),sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritol,lactitol, and xylitol), and starch hydrolysates (e.g., dextrins, andmaltodextrins).

The carbohydrate(s) may be present at level of about 5 percent to about95 percent of the powder blend/tablet, such as from about 20 percent toabout 90 percent or from about 40 percent to about 80 percent of thepowder blend/tablet. The particle size of the of carbohydrate caninfluence the level of meltable binder used, wherein a higher particlesize of carbohydrate provides a lower surface area and subsequentlyrequires a lower level of meltable binder. In one embodiment, whereinthe carbohydrate(s) is greater than 50% by weight of the powder blendand the mean particle size of the carbohydrate(s) is greater than 100microns, then the meltable binder is from about 10 to about 30 percentby weight of the powder blend/tablet.

Pharmaceutically Active Agent

The powder blend/tablet of the present invention includes at least onepharmaceutically active agent. What is meant by a “pharmaceuticallyactive agent” is an agent (e.g., a compound) that is permitted orapproved by the U.S. Food and Drug Administration, European MedicinesAgency, or any successor entity thereof, for the oral treatment of acondition or disease. Suitable pharmaceutically active agents include,but are not limited to, analgesics, anti-inflammatory agents,antipyretics, antihistamines, antibiotics (e.g., antibacterial,antiviral, and antifungal agents), antidepressants, antidiabetic agents,antispasmodics, appetite suppressants, bronchodilators, cardiovasculartreating agents (e.g., statins), central nervous system treating agents,cough suppressants, decongestants, diuretics, expectorants,gastrointestinal treating agents, anesthetics, mucolytics, musclerelaxants, osteoporosis treating agents, stimulants, nicotine, andsedatives.

Examples of suitable gastrointestinal treating agents include, but arenot limited to: antacids such as aluminum-containing pharmaceuticallyactive agents (e.g., aluminum carbonate, aluminum hydroxide,dihydroxyaluminum sodium carbonate, and aluminum phosphate),bicarbonate-containing pharmaceutically active agents,bismuth-containing pharmaceutically active agents (e.g., bismuthaluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate,and bismuth subnitrate), calcium-containing pharmaceutically activeagents (e.g., calcium carbonate), glycine, magnesium-containingpharmaceutically active agents (e.g., magaldrate, magnesiumaluminosilicates, magnesium carbonate, magnesium glycinate, magnesiumhydroxide, magnesium oxide, and magnesium trisilicate),phosphate-containing pharmaceutically active agents (e.g., aluminumphosphate and calcium phosphate), potassium-containing pharmaceuticallyactive agents (e.g., potassium bicarbonate), sodium-containingpharmaceutically active agents (e.g., sodium bicarbonate), andsilicates; laxatives such as stool softeners (e.g., docusate) andstimulant laxatives (e.g., bisacodyl); H2 receptor antagonists, such asfamotidine, ranitidine, cimetadine, and nizatidine; proton pumpinhibitors such as omeprazole, dextansoprazole, esomeprazole,pantoprazole, rabeprazole, and lansoprazole; gastrointestinalcytoprotectives, such as sucraflate and misoprostol; gastrointestinalprokinetics such as prucalopride; antibiotics for H. pylori, such asclarithromycin, amoxicillin, tetracycline, and metronidazole;antidiarrheals, such as bismuth subsalicylate, kaolin, diphenoxylate,and loperamide; glycopyrrolate; analgesics, such as mesalamine;antiemetics such as ondansetron, cyclizine, diphenyhydroamine,dimenhydrinate, meclizine, promethazine, and hydroxyzine; probioticbacteria including but not limited to lactobacilli; lactase;racecadotril; and antiflatulents such as polydimethylsiloxanes (e.g.,dimethicone and simethicone, including those disclosed in U.S. Pat. Nos.4,906,478, 5,275,822, and 6,103,260); isomers thereof; andpharmaceutically acceptable salts and prodrugs (e.g., esters) thereof.

Examples of suitable analgesics, anti-inflammatories, and antipyreticsinclude, but are not limited to, non-steroidal anti-inflammatory drugs(NSAIDs) such as propionic acid derivatives (e.g., ibuprofen, naproxen,ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen,fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, and suprofen)and COX inhibitors such as celecoxib; acetaminophen; acetyl salicylicacid; acetic acid derivatives such as indomethacin, diclofenac,sulindac, and tolmetin; fenamic acid derivatives such as mefanamic acid,meclofenamic acid, and flufenamic acid; biphenylcarbodylic acidderivatives such as diflunisal and flufenisal; and oxicams such aspiroxicam, sudoxicam, isoxicam, and meloxicam; isomers thereof; andpharmaceutically acceptable salts and prodrugs thereof.

Examples of antihistamines and decongestants, include, but are notlimited to, bromopheniramine, chlorcyclizine, dexbrompheniramine,bromhexane, phenindamine, pheniramine, pyrilamine, thonzylamine,pripolidine, ephedrine, phenylephrine, pseudoephedrine,phenylpropanolamine, chlorpheniramine, dextromethorphan,diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine,naphazoline, oxymetazoline, montelukast, propylhexadrine, triprolidine,clemastine, acrivastine, promethazine, oxomemazine, mequitazine,buclizine, bromhexine, ketotifen, terfenadine, ebastine, oxatamide,xylomeazoline, loratadine, desloratadine, and cetirizine; isomersthereof; and pharmaceutically acceptable salts and esters thereof.

Examples of cough suppressants and expectorants include, but are notlimited to, diphenhydramine, dextromethorphan, noscapine, clophedianol,menthol, benzonatate, ethylmorphone, codeine, acetylcysteine,carbocisteine, ambroxol, belladona alkaloids, sobrenol, guaiacol, andguaifenesin; isomers thereof; and pharmaceutically acceptable salts andprodrugs thereof.

Examples of muscle relaxants include, but are not limited to,cyclobenzaprine and chlorzoxazone metaxalone, orphenadrine, andmethocarbamol; isomers thereof; and pharmaceutically acceptable saltsand prodrugs thereof.

Examples of stimulants include, but are not limited to, caffeine.

Examples of sedatives include, but are not limited to sleep aids such asantihistamines (e.g., diphenhydramine), eszopiclone, and zolpidem, andpharmaceutically acceptable salts and prodrugs thereof.

Examples of appetite suppressants include, but are not limited to,phenylpropanolamine, phentermine, and diethylcathinone, andpharmaceutically acceptable salts and prodrugs thereof.

Examples of anesthetics (e.g., for the treatment of sore throat)include, but are not limited to dyclonine, benzocaine, and pectin andpharmaceutically acceptable salts and prodrugs thereof.

Examples of suitable statins include but are not limited to atorvastin,rosuvastatin, fluvastatin, lovastatin, simvustatin, atorvastatin,pravastatin and pharmaceutically acceptable salts and prodrugs thereof.

In one embodiment, the pharmaceutically active agent included within thetablet is selected from phenylephrine, dextromethorphan,pseudoephedrine, acetaminophen, cetirizine, aspirin, nicotine,ranitidine, ibuprofen, ketoprofen, loperamide, famotidine, calciumcarbonate, simethicone, chlorpheniramine, methocarbomal, chlophedianol,ascorbic acid, pectin, dyclonine, benzocaine and menthol, andpharmaceutically acceptable salts and prodrugs thereof.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of pharmaceutically acceptablesalts, such as acidic/anionic or basic/cationic salts. Pharmaceuticallyacceptable acidic/anionic salts include, and are not limited to acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphospate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate and triethiodide. Pharmaceutically acceptablebasic/cationic salts include, and are not limited to aluminum,benzathine, calcium, chloroprocaine, choline, diethanolamine,ethylenediamine, lithium, magnesium, meglumine, potassium, procaine,sodium and zinc.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of prodrugs of thepharmaceutically active agents. In general, such prodrugs will befunctional derivatives of the pharmaceutically active agent, which arereadily convertible in vivo into the required pharmaceutically activeagent. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, theinvention provides the esters, amides, and other protected orderivatized forms of the described compounds.

Where the pharmaceutically active agents according to this inventionhave at least one chiral center, they may accordingly exist asenantiomers. Where the pharmaceutically active agents possess two ormore chiral centers, they may additionally exist as diastereomers. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention. Furthermore, someof the crystalline forms for the pharmaceutically active agents mayexist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the pharmaceutically activeagents may form solvates with water (e.g., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention.

In one embodiment, the pharmaceutically active agent or agents arepresent in the tablet in a therapeutically effective amount, which is anamount that produces the desired therapeutic response upon oraladministration and can be readily determined by one skilled in the art.In determining such amounts, the particular pharmaceutically activeagent being administered, the bioavailability characteristics of thepharmaceutically active agent, the dose regime, the age and weight ofthe patient, and other factors must be considered, as known in the art.

The pharmaceutically active agent may be present in various forms. Forexample, the pharmaceutically active agent may be dispersed at themolecular level, e.g. melted, within the tablet, or may be in the formof particles, which in turn may be coated or uncoated. If thepharmaceutically active agent is in form of particles, the particles(whether coated or uncoated) typically have an average particle size offrom about 1 to about 2000 microns. In one embodiment, such particlesare crystals having an average particle size of from about 1 to about300 microns. In another embodiment, the particles are granules orpellets having an average particle size of from about 50 to about 2000microns, such as from about 50 to about 1000 microns, such as from about100 to about 800 microns.

The pharmaceutically active agent may be present in pure crystal form orin a granulated form prior to the addition of the taste masking coating.Granulation techniques may be used to improve the flow characteristicsor particle size of the pharmaceutically active agents to make it moresuitable for compaction or subsequent coating. Suitable binders formaking the granulation include but are not limited to starch,polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose,and hydroxypropylcellulose. The particles including pharmaceuticallyactive agent(s) may be made by cogranulating the pharmaceutically activeagent(s) with suitable substrate particles via any of the granulationmethods known in the art. Examples of such granulation method include,but are not limited to, high sheer wet granulation and fluid bedgranulation such as rotary fluid bed granulation.

If the pharmaceutically active agent has an objectionable taste, thepharmaceutically active agent may be coated with a taste maskingcoating, as known in the art. Examples of suitable taste maskingcoatings are described in U.S. Pat. No. 4,851,226, U.S. Pat. No.5,075,114, and U.S. Pat. No. 5,489,436. Commercially available tastemasked pharmaceutically active agents may also be employed. For example,acetaminophen particles, which are encapsulated with ethylcellulose orother polymers by a coacervation process, may be used in the presentinvention. Coacervation-encapsulated acetaminophen may be purchasedcommercially from Eurand America, Inc. (Vandalia, Ohio) or from CircaInc. (Dayton, Ohio).

In one embodiment, the tablet incorporates modified release coatedparticles (e.g., particles containing at least one pharmaceuticallyactive agent that convey modified release properties of such agent). Asused herein, “modified release” shall apply to the altered release ordissolution of the active agent in a dissolution medium, such asgastrointestinal fluids. Types of modified release include, but are notlimited to, sustained release or delayed release. In general, modifiedrelease tablets are formulated to make the active agents(s) availableover an extended period of time after ingestion, which thereby allowsfor a reduction in dosing frequency compared to the dosing of the sameactive agent(s) in a conventional tablet. Modified release tablets alsopermit the use of active agent combinations wherein the duration of onepharmaceutically active agent may differ from the duration of anotherpharmaceutically active agent. In one embodiment the tablet contains onepharmaceutically active agent that is released in an immediate releasemanner and an additional active agent or a second portion of the sameactive agent as the first that is modified release.

Examples of swellable, erodible hydrophilic materials for use as arelease modifying excipient for use in the modified release coatinginclude water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, and gelling starches. Examples of water swellable cellulosederivatives include sodium carboxymethylcellulose, cross-linkedhydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose. Examplesof polyalkylene glycols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkylene oxides include poly (ethyleneoxide). Examples of acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, andhigh-molecular weight cross-linked acrylic acid homopolymers andcopolymers.

Suitable pH-dependent polymers for use as release-modifying excipientsfor use in the modified release coating include: enteric cellulosederivatives such as hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, and cellulose acetatephthalate; natural resins such as shellac and zein; enteric acetatederivatives such as polyvinylacetate phthalate, cellulose acetatephthalate, and acetaldehyde dimethylcellulose acetate; and entericacrylate derivatives such as for example polymethacrylate-based polymerssuch as poly(methacrylic acid, methyl methacrylate) 1:2 (available fromRohm Pharma GmbH under the tradename EUDRAGIT S) and poly(methacrylicacid, methyl methacrylate) 1:1 (available from Rohm Pharma GmbH underthe tradename EUDRAGIT L).

In one embodiment the pharmaceutically active agent is coated with acombination of a water insoluble film forming polymer (such as but notlimited to cellulose acetate or ethylcellulose) and a water solublepolymer (such as but not limited to povidone, polymethacrylicco-polymers such as those sold under the tradename Eudragit E-100 fromRohm America, and hydroxypropylcellulose). In this embodiment, the ratioof water insoluble film forming polymer to water soluble polymer is fromabout 50 to about 95 percent of water insoluble polymer and from about 5to about 50 percent of water soluble polymer, and the weight percent ofthe coating by weight of the coated taste-masked particle is from about5 percent to about 40 percent. In one embodiment, the coating which isused in the coated particle of the pharmaceutically active agent issubstantially free of a material (such as polyethylene glycol) whichmelts below 85° C., in order to prevent damage to the integrity of thecoating during the RF heating step.

In one embodiment, one or more pharmaceutically active agents or aportion of the pharmaceutically active agent may be bound to an ionexchange resin for the purposes of taste-masking the pharmaceuticallyactive agent or delivering the active in a modified release manner.

In one embodiment, the pharmaceutically active agent is capable ofdissolution upon contact with a fluid such as water, stomach acid,intestinal fluid or the like. In one embodiment, the dissolutioncharacteristics of the pharmaceutically active agent within the tabletmeets USP specifications for immediate release tablets including thepharmaceutically active agent. For example, for acetaminophen tablets,USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2(paddles) at 50 rpm, at least 80% of the acetaminophen contained in thetablet is released there from within 30 minutes after dosing, and foribuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer,using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofencontained in the tablet is released there from within 60 minutes afterdosing. See USP 24, 2000 Version, 19-20 and 856 (1999). In anotherembodiment, the dissolution characteristics of the pharmaceuticallyactive agent are modified: e.g. controlled, sustained, extended,retarded, prolonged, delayed and the like.

In one embodiment, the particle size of the pharmaceutically activeagent causes more void spaces to be present in the tablet, wherein ahigher particle size of the pharmaceutically active agent subsequentlyrequires a lower level of meltable binder. In one embodiment, whereinthe pharmaceutically active agent or coated pharmaceutically activeagent(s) is greater than 50% of the blend by weight of the powderblend/tablet and the mean particle size of the carbohydrate is greaterthan 100 microns, the meltable binder is from about 10 to about 30percent by weight of the powder blend/tablet. In one embodiment, whereinthe mean particle size of the powder blend is between about 100 micronsand about 300 microns, then meltable binder is from about 10 to about 20percent by weight of the powder blend/tablet.

The melting point of the pharmaceutically active agent can have animpact on the temperature used during the heating step and the type ofmeltable binder used. In one embodiment, the melting point of themeltable binder is less than the melting point of the pharmaceuticallyactive agent. In another embodiment, the melting point of thepharmaceutically active agent is the same or lower than the meltingpoint of the meltable binder, in which case during the fusing or heatingstep, both the pharmaceutically active agent and the meltable binder maymelt and create a eutectic or various bridges of the pharmaceuticallyactive agent and meltable binder between the other materials in thetablet form upon cooling. In one embodiment, the heating temperature isabove the melting point of the meltable binder and below the meltingpoint of the pharmaceutically active agent. In one embodiment whereinibuprofen is the pharmaceutically active agent, the meltable binder isheated from about 30° C. to about 60° C. In one embodiment, thepharmaceutically active agent is the meltable binder.

In one embodiment, the pharmaceutically active agent is in the form of aparticle that is coated with the binder. Examples of such binder coatedparticles include, but are not limited to, meltable materials such asglyceryl palmitostearate.

The susceptibility to RF energy of the pharmaceutically active agent(e.g., to melt or degrade) can have an impact on the type of energyand/or temperature used during the heating step as well as the type ofthe meltable binder used.

In one embodiment, the processing of the tablet is free of a wet or hotmelt granulation step. In this embodiment, the materials are directlyblended prior to the addition of heat. In one embodiment, the materialsare directly blended and compressed prior to the addition of heat.

Manufacture of Tablet Shape

In one embodiment, the tablet shape is pre-formed by light compaction.In one embodiment, the powder blend is fed into the tablet die of anapparatus that applies pressure to form the tablet shape (e.g., by lightcompaction such as tamping). Any suitable compacting apparatus may beused, including, but not limited to, a conventional unitary or rotarytablet press. In one embodiment, the tablet shape may be formed bycompaction using a rotary tablet press (e.g., such as those commerciallyavailable from Fette America Inc., Rockaway, N.J. or Manesty MachinesLTD, Liverpool, UK). In one embodiment, the tablet shape is heated afterit is removed from the tablet press. In another embodiment, the tabletshape is heated within the tablet press.

In one embodiment, to obtain desired attribute of an orallydisintegrating tablet, the tablet's construction may be highly porous,use a minimal amount of binder, and/or have a low density. Such tablets,therefore, are somewhat fragile and soft. In a preferred embodiment, aminimum of tamping/compaction force is desired to achieve the orallydisintegrating property (low density). Experiments have determined thatlow force compaction without application of energy produced very fragiletablets that could not withstand the forces of material handlingrequired in manufacturing.

In most thermodynamic processes or machines, the heat source and theheat sink are two distinct machines or steps requiring material to betransferred from one apparatus to the other. In the manufacture of thetablets of the present invention, the energy must be added to the tabletto achieve the binding effect and then must be removed from the productto solidify and strengthen it for its final handling packaging and use.One of the unique and unanticipated attributes of one embodiment of themanufacturing process of the present invention is that heat source andheat sink are part of the same apparatus. In fact in early experimentsthe metallic forming tool (e.g., a die punch) which was at roomtemperature removed so much heat from the treated tablet shape (due toits high thermal conductivity) that the surface of the resulting tabletwas unacceptable due to the fact that uniform melting within the powderblend had not taken place. The resulting tablet had a well formed core,but the surface was loose unbound and poorly formed powder that did notadhere to the rest of the tablet. To correct for this thermal loss, inone embodiment, heat is added to the forming tools to achieve propersintering at the surface as well as at the center of the tablet.

To exploit this unique thermal effect, powder blends can also be chosenfor their thermal properties and thermal conductivity and specific heatsuch that the powder blend particles themselves become heat sinks. Forexample, in a typical ODT formulation the polar binders that heat in theRF field may compose less than 10% of the mixture. The remaining 90% ofthe materials act as a heat sink that quickly removes heat from thebinders once the RF field is removed. The desirable result of this isthat the total process time can be just a few seconds and that thetablet does not need to be transferred from the die platen during thecritical tamping and heating process. The die platen can function thenas a material handling apparatus as well as a thermal forming tool. Thisis particularly advantageous for successful manufacture of fragileorally disintegrating tablets.

In one embodiment, the compaction step (e.g., tamping) which occursprior to the addition of the energy utilizes a compaction force which isless than the force required to compress a chewable or swallowabletablet. In one embodiment, the compaction force is less than about 1000pounds per square inch (e.g., less than about 500 pounds per squareinch, such as less than 200 pounds per square inch, such as less than 50pounds per square inch). In one embodiment, the energy is applied whilethe powder blend is under such force.

In one embodiment, the compaction step occurs in an indexed manner,where one set of tablets are compacted simultaneously, before rotatingto another indexing station. In one embodiment, the compaction stepoccurs at a single indexing station and the application of energy occursat a separate indexing station. In another embodiment, a third indexingstation is present wherein the ejection of the tablet or multipletablets occurs, wherein the lower forming tool is raised up through andup to the surface of the die. In another embodiment the compaction stepis performed through the addition of air pressure or hydraulic cylinderto the top of the upper forming tools. In one embodiment multipletablets are ejected simultaneously and separated from the surface of theindexing station and removed via a take-off bar.

In another embodiment, the tablet shape may be prepared by thecompaction methods and apparatus described in United States PatentApplication Publication No. 20040156902. Specifically, the tablet shapemay be made using a rotary compression module including a fill zone,insertion zone, compression zone, ejection zone, and purge zone in asingle apparatus having a double row die construction. The dies of thecompression module may then be filled using the assistance of a vacuum,with filters located in or near each die. The purge zone of thecompression module includes an optional powder blend recovery system torecover excess powder blend from the filters and return the powder blendto the dies. In one embodiment the energy source (e.g., RF energysource) is projected through the die table of a rotary press into theappropriate electrode within the forming tool or the forming cavity. Inone embodiment the die table is constructed of non-conductive material.

In another embodiment, a portion of the tablet shape may be prepared bya wet-granulation method, in which the excipients and a solution ordispersion of a wet binder (e.g., an aqueous cooked starch paste orsolution of polyvinyl pyrrolidone) are mixed and granulated. Suitableapparatus for wet granulation include low shear mixers (e.g., planetarymixers), high shear mixers, and fluid beds (including rotary fluidbeds). The resulting granulated material may then be dried, andoptionally dry-blended with further ingredients (e.g., excipients suchas, for example, the binders described in the invention herein,lubricants, colorants, and the like). The final dry blend is thensuitable for compaction by the methods described herein. Methods fordirect compaction and wet granulation processes are known in the art.

In one embodiment, the tablet shape is prepared by the compactionmethods and apparatus described in issued U.S. Pat. No. 6,767,200.Specifically, the tablet shape is made using a rotary compression moduleincluding a fill zone, compression zone, and ejection zone in a singleapparatus having a double row die construction as shown in FIG. 6therein. The dies of the compression module are preferably filled usingthe assistance of a vacuum, with filters located in or near each die.

The tablet shape may have one of a variety of different shapes. Forexample, the tablet shape may be shaped as a polyhedron, such as a cube,pyramid, prism, or the like; or may have the geometry of a space figurewith some non-flat faces, such as a cone, truncated cone, triangle,cylinder, sphere, torus, or the like. In certain embodiments, a tabletshape has one or more major faces. For example, the tablet shape surfacetypically has opposing upper and lower faces formed by contact with theupper and lower forming tool faces (e.g., die punches) in the compactionmachine. In such embodiments, the tablet shape surface typically furtherincludes a “belly-band” located between the upper and lower faces, andformed by contact with the die walls in the compaction machine. A tabletshape/tablet may also be a multilayer. Applicants have found that sharpedges in the tooling used to make the tablets can cause arcing, and thusmore rounded edges may be needed.

In one embodiment, the method of producing the tablet shape issubstantially free of the use of solvents. In this embodiment, thepowder blend is substantially free of solvents, and the manufacturingprocess (e.g., filling process into the die) is also substantially freeof solvents. Solvents may include, but are not limited to, water,organic solvents such as but not limited to alcohols, chlorinatedsolvents, hexanes, or acetone; or gaseous solvents such as but notlimited to nitrogen, carbon dioxide or supercritical fluids.

In one embodiment a vibratory step is utilized (e.g., added afterfilling of the powder blend but prior to the heating or fusing step, inorder to remove air from the powder blend). In one embodiment avibration with the frequency from about 1 Hz to about 50 KHz is addedwith amplitude from 1 micron to 5 mm peak-to-peak to allow for theflowable powder blend to settle into the cavity of a the die platen(“forming cavity”).

In one embodiment, as shown in FIGS. 1A-1F, a metered volume of powderblend 4 is filled into a Teflon® (or similar electrical and RF energyinsulative material such as ceramic or UHMW plastic) die platen 2. Dieplaten 2 has forming cavity 5 with inner wall 6, upper opening 7 on theupper surface of die platen 2 (which allows powder blend 4 and upperforming tool 1 to move into the forming cavity 5), and lower opening 8on the opposite surface of die platen 2 (which allows powder blend 4 andlower forming tool 3 to move into the forming cavity 5). Powder blend 4may be either gravity fed or mechanically fed from a feeder (not shown).A metallic, electrically conductive lower forming tool 3 is insertedinto the die platen to retain the powder blend 4, within die platen 2. Asimilar metallic, electrically conductive upper forming tool 1 ispositioned above the die platen 2 as shown in FIG. 1B. The forming tools1 and 3, die platen 2, and powder blend 4 are then moved to a compactionand RF heating station as shown in FIG. 1C to form tablet shape 4 a.

This heating station is comprised of an RF generator 7 which producesthe necessary high voltage, high frequency energy. The generator 7 iselectrically connected to movable upper RF electrode plate 8 and movablelower RF electrode plate 6. As shown in FIG. 1C, at this position, thepowder blend 4 is compacted between an upper forming tool 1 and a lowerforming tool 3 by pressure exerted by upper RF electrode plate 8 andlower electrode plate 6 to form tablet shape 4 a. Tablet shape 4 a isthen exposed to RF energy from RF generator 7, which heats the meltablebinder within tablet shape 4 a. After the RF energy is switched off,tablet shape 4 a cools to form the tablet 4 b. In one embodiment, asshown in FIG. 1D, tablet 4 b is pushed by upper forming tool 1 from thedie platen 2 into blister 8, which is used to package tablet 4 b. In analternative embodiment, as shown in FIG. 1E, tablet 4 b is pushed fromthe die platen 2 by the lower forming tool 3 and guided to an ejectionchute by a stationary “take-off” bar (not shown). FIG. 1F shows a 3dimensional representation of the forming tools 1 and 4, die platen 2,and tablet 4 b.

In FIGS. 2A-2H, an alternate embodiment of the invention is shown wherea multilayer tablet is produced. First, powder blend 10 is filled intodie platen 2 as shown in FIG. 2A. Powder blend 10 is tamped or moveddown into die platen 2 by upper forming tool 1 as shown in FIG. 2B toform tablet shape 10 a. Then, powder blend 11 is then filled on top oftablet shape 10 a. The forming tools 1 and 3, die platen 2, tablet shape10 a and powder blend 11 are then moved to the compaction and RF heatingstation as shown in FIG. 2E. RF heating is accomplished as describedabove in FIG. 1C to produce multilayer tablet 12 as shown in FIGS. 2Fand 2G. While a bi-layer tablet is shown in the drawing, additionalmultiple layers can be produced by adding additional powder blends todie platen 2.

FIGS. 3A-3G show another embodiment of the invention where preformedinserts 30 and 31 are inserted into tablet shape 20 a as shown in FIGS.3A-3D. Forming tools 1 and 3, die platen 2, tablet shape 20, andpreformed inserts 30 and 31 are then moved to the compaction and RFheating station as shown in FIG. 3E. RF heating is accomplished asdescribed above in FIG. 1C to produce a multi-component tablet 40 shownin FIGS. 2F and 2G.

FIGS. 4A and 4B show two views of a rotary indexing machine 195 which isdesigned to create large quantities of tablets. In particular, theconfiguration of the apparatus shown is designed to manufacture fragiletablets with minimized risk of damaging them as they are moved throughthe various manufacturing steps. This embodiment of the invention iscomprised of an indexing table 170 having four sets of die platens 175each having sixteen cavities, powder feeder 100, RF generator 150, amachine frame 140, moving RF electrode assemblies 120 and 130, lowerforming tool assembly 110, upper forming tool assembly 210, tabletejection station 160, indexer drive system 180, blister package web 190,and blister lid material roll 191.

FIG. 5A is a top view of the apparatus in the dwell position. FIG. 5B isa top view of the apparatus as the indexing table 170 rotates betweenstations in direction “A”. FIG. 6A depicts a section view through thelower forming tool assembly 110 in a start position of the manufacturingcycle. The lower forming tools 111, which are made of an electricallyconductive metallic material such as brass or stainless steel, areretained in retainer plate 112 (e.g., made of aluminum or steel). Heatedblock 117 is attached to the retainer plate 112 and contains fluidpassages 117 b. Heated (or optionally cooling) fluid is circulatedthrough the heated block 117 by connections to flexible hoses 119 a and119 b which form a supply and return circuit. Heating can also beaccomplished by electric cartridge heaters or other suitable means (notshown). Attached to the retainer plate are cam-follower 114 and linearbearing 113. A guide shaft 116 is fixed to indexing table 170. Theretainer plate and forming tools 111 and are moveable up or downaccording to the profile of barrel cam 115 which cam follower 114 rollsupon. Also shown is die platen 171, which is made of electrical and RFenergy insulative material such as Teflon, UHMW, or ceramic. This isnecessary to prevent a short circuit when the electrically conductiveforming tools are positioned in the RF electric field in subsequentsteps. The forming cavity 171 a is shown empty at this stage of theprocess.

FIG. 6B depicts a section through the powder feeder station 100 of theapparatus. In this station powdered powder blend 101 is gravity fed intodie platen 171. Movable cam segment 118 is adjusted up or down indirection “B” to vary the volume of the forming cavity 171 a by changingthe amount that the lower forming tools 111 penetrate into the dieplaten 171. This adjustable volume feature enables the precise dose ofpowdered powder blend to be selected for a desired tablet weight. Whenthe machine indexes out of the powder feeder station, the rim of feeder102 scrapes against the die platen 171 to create a level powder surfacerelative to the surface of the die platen 171.

FIG. 7 is a section view through the RF station of the apparatus. The RFgenerator 150 is depicted symbolically here. In one embodiment, theconfiguration of the RF generator 150 is a free running oscillatorsystem. It is typically composed of a power vacuum tube (such as atriode), a DC voltage source between 1000 and 8000 volts connectedacross the cathode and plate (anode). A tank circuit is used to impose asinusoidal signal upon the control grid and electrodes thereby producingthe necessary frequency (typically 13.56 MHZ or 27.12 MHZ) and highvoltage field. An example of such RF generator 150 is the COSMOS ModelC10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, N.Y.). Inanother embodiment, RF energy can be provided by a 50 Ohm systemcomposed of a waveform generator which feeds a radio frequency signal topower amplifiers which are coupled to the electrodes and the load by animpedance matching network.

In FIG. 7, a lower movable RF electrode 121 is shown, movable indirection “D”. It is represented in its down position. The linearmovement is generated by linear actuators which are typically devisessuch as air cylinders or servo motors. Two air cylinders are depicted inFIG. 7. Air cylinder bodies 141 and 142 apply pressure to guide rods 144and 143. Moving platens 132 and 122 are connected to the guide rods andprovide an electrically isolated mounting for electrode plates 131 and121. RF generator 150 connects to the electrode plates 131 and 121through wires 185 and 184. A movable upper RF electrode assembly 130,movable in direction “C”, is shown in its up position. Upper formingtools 133, retainer plate 134, and heated block 135 are all attached tothe movable RF electrode plate 131 and, consequently, move up and downwith it. Powder blend 101 is within die platen 171.

FIG. 8 is a section through the same RF station but shows the RFelectrodes 131 and 121 pressing against the respective forming toolassemblies 133 and 111 to both compact and apply RF energy to powderblend 101 creating tablet 101 a. After application of the RF energy isstopped, the moveable RF electrode plates retract, and the indexingplate 170, die platen 171, and lower forming tool assembly 110 areindexed to the next station.

FIG. 9 is a section view through the tablet ejection station 160.Ejector pins 161 are attached to movable plate 162 (movable in the “E”direction), which is actuated by actuator assembly 163 (for example,this can be a linear servo motor or air cylinder or other suitableactuator). Actuator rod 166 connects to the movable plate 162. Linearbearing 164 and guide rod 165 provide rigidity and support for theactuator plate 162 and prevent destructive side loads created by theejection force from acting upon actuator 163. A blister package 190 isshown below die platen 171.

FIG. 10 is a section through the same assembly after the ejector pins161 have pushed finished tablets 101 a through the die platen 171. Thisdirect placement of tablet into blister helps prevent breakage thatcould occur while using typical means such as feeders or by dumpingtablets into transport drums.

In one embodiment, a lubricant is added to forming cavity prior to theaddition of the flowable powder blend. This lubricant may be a liquid orsolid. Suitable lubricants include but are not limited to solidlubricants such as magnesium stearate, starch, calcium stearate,aluminum stearate and stearic acid; or liquid lubricants such as but notlimited to simethicone, lecithin, vegetable oil, olive oil, or mineraloil. In certain embodiments, the lubricant is added at a percentage byweight of the tablet of less than 5 percent, e.g. less than 2 percent,e.g. less than 0.5 percent. In certain embodiments, the presence of ahydrophobic lubricant can disadvantageously compromise thedisintegration or dissolution properties of a tablet. In one embodimentthe tablet is substantially free of a hydrophobic lubricant. Hydrophobiclubricants include magnesium stearate, calcium stearate and aluminumstearate.

Heating of Tablet Shape to Form Tablet

Various forms of energy may be used in the process to activate thebinder. Suitable sources of energy include but are not limited toconvection, radio frequency, microwave, UV light, infrared, induction,laser light, and ultrasonic sound. In one embodiment, radiofrequencyenergy is used. Radiofrequency heating generally refers to heating withelectromagnetic field at frequencies from about 1 MHz to about 100 MHz.In one embodiment of the present invention, the RF-energy is within therange of frequencies from about 1 MHz to about 100 MHz (e.g., from about5 MHz to 50 MHz, such as from about 10 MHz to about 30 MHz).

In one embodiment, RF-energy is used to heat the binder (e.g., eitherdirectly when the meltable binder is a RF-meltable binder or indirectlywhen the meltable binder is not a RF meltable binder but is heated by aRF-heatable ingredient within the powder blend). The degree ofcompaction, the type and amount of meltable binder, and the amount of RFenergy used can determine the hardness and/or type of tablet whether anoral disintegrating tablet or a soft chewable tablet is manufactured.

RF energy generators are well known in the art. Examples of suitable RFgenerators include, but are not limited to, COSMOS Model C10X16G4(Cosmos Electronic Machine Corporation, Farmingdale, N.Y.).

The energy (e.g., RF energy) is used to activate the binder. The degreeof compaction, the type and amount of binder, and the amount of energyused can determine the hardness and/or type of tablet.

In one embodiment, when RF energy is used, the upper and lower formingtools serve as the electrodes (e.g., they are operably associated withthe RF energy source) through which the RF energy is delivered to thetablet shape. In one embodiment, there is direct contact between atleast one RF electrode (e.g., forming tool) and the tablet shape. Inanother embodiment, there is no contact between any of the RF electrode(e.g., forming tools) and the tablet shape. In one embodiment, the RFelectrodes are in direct contact with the surface of the tablet shapewhen the RF energy is added. In another embodiment, the RF electrodesare not in contact (e.g., from about 1 mm to about 1 cm from the surfaceof the tablet shape) during the addition of the RF energy.

In one embodiment, the RF energy is delivered while the tablet shape isbeing formed. In one embodiment, the RF energy is delivered once thetablet shape is formed. In one embodiment, the RF energy is deliveredafter the tablet shape has been removed from the die.

In one embodiment, the RF energy is applied for a sufficient time tosoften and melt substantially all (e.g., at least 90%, such as at least95%, such as all) of the binder within the tablet shape. In oneembodiment, the RF energy is applied for a sufficient time to soften andmelt only a portion (e.g., less than 75%, such as less than 50%, such asless than 25%) of the binder within the tablet shape, for example onlyon a portion of the tablet shape, such as the outside of the tabletshape.

In alternate embodiments of the invention, the forming tools can beconstructed to achieve localized heating effects and can also beconfigured to shape the electric field that is developed across thetools. FIG. 11A shows one such configuration. An RF generator 200 isconnected to RF electrode plates 201 and 202. Forming tools 205 and 204are constructed of an electrically conductive material and they have anattachment 207 and 208 which are made of electrical and RF energyinsulative material such as ceramic, Teflon®, polyethylene, or highdensity polyethylene. Die platen 203 is also constructed of electricaland RF energy insulative material. This configuration creates greaterdistance between the conductive forming tools to weaken the electricfield which is beneficial for producing thin tablets without the risk ofan electric arc forming which would damage the product and tooling. FIG.11B depicts a similar configuration but with forming tools 210 and 211that, respectively, have a recess containing insert 213 and 212 whichare made of electrical and RF energy insulative material. This geometrywill produce a tablet with lesser heating in the area where the inserts213 and 212 are located since the electric field is weaker due to thegreater distance between the conductive portions of 211 and 210. FIG.11C is similar to FIG. 11B only the geometry is reversed so the tabletformed by this configuration will have a greater heating effect at thecenter since the inserts 216 and 217 are at the periphery of respectiveforming tools 214 and 215. FIG. 11D depicts another embodiment wherebythe die platen is constructed of an electrically conductive component221 and electrically insulating component 222, which is made ofelectrical and RF energy insulative material. Forming tools 219 and 218are electrically conductive, but forming tool 218 further containssecond electrically insulating component 220 around the surface of upperforming tool 218 which contact tablet shape 206. This configurationcreates an electric field and associated zones of heating that ispreferential to the conductive portions of the die platen.

FIG. 12A is similar to FIG. 11D except the die platen 233 in thisembodiment is constructed entirely of electrically conductive material.FIGS. 12B and 12C depict two embodiments where the die platen comprisesa respective center portion 245 and 254 that are electrically conductiveand respective outer portions 244/246 and 252/253 is are made ofelectrical and RF energy insulative material. FIG. 12B further includesinsulating component 220 around the surface of lower forming tool 219.FIG. 12D is a further embodiment where the forming tools 263 and 262 aremade of electrical and RF energy insulative material. The die platenportions 264 and 265 are made of electrical and RF energy insulativematerial, but there are two respective electrically conductive portions267 and 266 which are attached to the RF generator circuit 200. In thisconfiguration, the electric field is applied in the horizontal directionacross the tablet shape 206.

As described above, the distance between conductive portions of theforming tool has a strong effect on field strength and heating effect.To create a tablet with uniform heating and texture, a forming tool thatis constructed with equidistant spacing is desirable. FIGS. 13A and 13Bdepict such a configuration. In this embodiment, a wave-shaped formingtools 270 and 273 are shown to create a tablet 272 within die platen 271with a unique appearance. The profiles of the forming tool surfaces areequidistant as shown by dimension “X”.

FIG. 14A is an embodiment wherein a non-uniform heating is used tomanufacture tablet 282. In this embodiment, a tablet with hard and softzones is created. The forming tools 280 and 281 are made withprotrusions at the surface that create high field strength (resulting ingreater heating) where they are closest together (shown by the dimension“Z”) and weaker field strength (resulting in lesser heating) where theyare further apart (shown by the dimension “Y”).

In one embodiment, to help reduce sticking, the tablet is cooled withinthe forming cavity to cool and/or solidify the binder. The cooling canbe passive cooling (e.g., at room temperature) or active cooling (e.g.,coolant recirculation cooling). When coolant recirculation cooling isused, the coolant can optionally circulate through channels inside theforming tools (e.g., punches or punch platen) and/or die or die platen(e.g., as discussed above in FIGS. 6A and 6B). In one embodiment, theprocess uses a die platen having multiple die cavities and upper andlower punch platens having multiple upper and lower punched forsimultaneous forming of a plurality of tablets wherein the platens areactively cooled.

In one embodiment, there is a single powder blend forming the tabletshape which is then heated with the RF energy. In another embodiment,the tablet is formed of at least two different powder blends, at leastone powder blend being RF-curable and at least one formulation being notRF-curable. When cured with RF energy, such tablet shape develops two ormore dissimilarly cured zones. In one embodiment, the outside area ofthe tablet shape is cured, while the middle of the tablet shape is notcured. By adjusting the focus of the RF heating and shape of the RFelectrodes, the heat delivered to the tablet shape can be focused tocreate customized softer or harder areas on the finished tablet.

In one embodiment the RF energy is combined with a second source of heatincluding but not limited to infrared, induction, or convection heating.In one embodiment, the addition of the second source of heat isparticularly useful with a secondary non-RF-meltable binder present inthe powder blend.

In one embodiment, the level of energy applied to the tablet iscontrolled by monitoring and controlling the frequency of theapplication of the RF energy. In one embodiment, the powder blend issealed within a chamber during the step with which the energy isapplied, so that the water is contained and can be distributedthroughout the powder blend. In one version of this embodiment, thesealed chamber consists of a die, and at least one heat source (e.g., RFapplying electrode). In one embodiment, upon opening of the sealedchamber, the fused tablet is further dried in order to allow for thewater to escape. This drying step may be achieved using the energysource or another source of heat.

In one embodiment, microwave energy is used (e.g., in place ofradiofrequency energy) to manufacture the tablet. Microwave heatinggenerally refers to heating with electromagnetic field at frequenciesfrom about 100 MHz to about 300 GHz. In one embodiment of the presentinvention, the RF-energy is within the range of frequencies from about500 MHz to about 100 GHz (e.g., from about 1 GHz to 50 GHz, such as fromabout 1 GHz to about 10 GHz). The microwave energy is used to heat thebinder (e.g., either directly when the meltable binder is susceptible tomicrowave energy (“microwave meltable binder”) or indirectly when themeltable binder is not a microwave meltable binder but is heated by amicrowave heatable ingredient within the powder blend. In such anembodiment, a microwave energy source and microwave electrodes are usedin the machine used to manufacture the dosage form.

Inserts within Tablet Shape

In one embodiment, an insert is incorporated into the tablet shapebefore the energy is delivered. Examples include solid compressed formsor beads filled with a liquid composition. Such incorporation of aninsert is depicted in FIGS. 3A-3G.

In one embodiment the pharmaceutically active agent is in the form of agel bead, which is liquid filled or semi-solid filled. The gel bead(s)are added as a portion of the powder blend. In one embodiment, thetablet of this invention has the added advantage of not using a strongcompaction step, allowing for the use of liquid or semisolid filledparticles or beads which are deformable since they will not rupturefollowing the reduced pressure compaction step. These bead walls maycontain gelling substances such as: gelatin; gellan gum; xanthan gum;agar; locust bean gum; carrageenan; polymers or polysaccharides such asbut not limited to sodium alginate, calcium alginate, hypromellose,hydroxypropyl cellulose and pullulan; polyethylene oxide; and starches.The bead walls may further contain a plasticizer such as glycerin,polyethylene glycol, propylene glycol, triacetin, triethyl citrate andtributyl citrate. The pharmaceutically active agent may be dissolved,suspended or dispersed in a filler material such as but not limited tohigh fructose corn syrup, sugars, glycerin, polyethylene glycol,propylene glycol, or oils such as but not limited to vegetable oil,olive oil, or mineral oil.

In one embodiment, the insert is substantially free of RF-absorbingingredients, in which case application of the RF energy results in nosignificant heating of the insert itself. In other embodiments, theinsert contains ingredients and are heated upon exposure to RF energyand, thus, such inserts can be used to soften or melt the meltablebinder.

Multi-Layer Tablet

In certain embodiments, the tablet includes at least two layers, e.g.,with different types and/or concentrations of binders and/or otheringredients or different concentrations of pharmaceutically activeagents. Such an embodiment is shown in FIGS. 2A-2D. In one embodiment,the tablet includes two layers, one layer having orally disintegratingproperties and another layer being chewable or swallowable. In oneembodiment, one layer has a meltable binder and another layer does nothave a meltable binder. In one embodiment one layer is compacted athigher compaction force versus the other layer. In one embodiment, bothlayers contain same amount of binder, but have different amount ofpharmaceutically active agents and/or other excipients. In oneembodiment, all properties of the two layers are identical but thecolors and/or flavors of the two layers are different. In oneembodiment, one layer disintegrates faster (e.g., at least two timefaster) then the other layer. In one embodiment, the tablet containsthree layers, wherein the composition of the third layer is differentfrom the composition of the first layer and the second layer.

In one embodiment, the tablet comprises two layers, wherein both thefirst layer and the second layer include a pharmaceutically activeagent. In one embodiment, the first layer and the second layer comprisedifferent pharmaceutically active agents. In one embodiment, theycontain the same pharmaceutically active agent, but in one layer, thepharmaceutically active agent is released in a modified manner.

Such multilayer tablets can be made by various means. In one embodiment,the process includes the steps of (i) adding a first powder blend to adie platen, wherein the first powder blend includes a pharmaceuticallyactive agent and a binder; (ii) adding a second powder blend to the dieplaten, wherein the second powder blend includes a binder and whereinthe composition of the second powder blend is different from thecomposition of the first powder blend; (iii) compacting a first powderblend and a second powder blend in the die platen to form a tabletshape; and (iv) applying energy to the tablet shape for a sufficientperiod of time to activate the binders within the tablet shape to fusethe tablet shape into the tablet. In one embodiment, first powder blendincludes particles containing the pharmaceutically active agent whereinthe particles are coated with the binder. In on embodiment, the processincludes compacting said the previously added powder blend prior toadding the next powder blend to the die platen.

Effervescent Couple

In one embodiment, the powder blend further contains one or moreeffervescent couples. In one embodiment, effervescent couple containsone member from the group consisting of sodium bicarbonate, potassiumbicarbonate, calcium carbonate, magnesium carbonate, and sodiumcarbonate, and one member selected from the group consisting of citricacid, malic acid, fumaric acid, tartaric acid, phosphoric acid, andalginic acid.

In one embodiment, the combined amount of the effervescent couple(s) inthe powder blend/tablet is from about 2 to about 20 percent by weight,such as from about 2 to about 10 percent by weight of the total weightof the powder blend/tablet.

Orally Disintegrating Tablet

In one embodiment, the tablet is designed to disintegrate in the mouthwhen placed on the tongue in less than about 60 seconds, e.g. less thanabout 45 seconds, e.g. less than about 30 seconds, e.g. less than about15 seconds.

In one embodiment, the tablet meets the criteria for OrallyDisintegrating Tablets (ODTs) as defined by the draft Food and DrugAdministration guidance, as published in April, 2007. In one embodiment,the tablet meets a two-fold definition for orally disintegrating tabletsincluding the following criteria: 1) that the solid tablet is one whichcontains medicinal substances and which disintegrates rapidly, usuallywithin a matter of seconds, when placed upon the tongue and 2) beconsidered a solid oral preparation that disintegrates rapidly in theoral cavity, with an in vitro disintegration time of approximately 30seconds or less, when based on the United States Pharmacopeia (USP)disintegration test method for the specific medicinal substance orsubstances.

Additional Edible Portion

In one embodiment, the tablet is contained next to another edible form.In one embodiment, this edible form is a hard candy or compressed ringthat holds the powder blend during compaction and/or the RF heatingstep.

In one embodiment, the outer hard candy form may be made using uniplastrolling or roping and subsequent cutting and stamping, as well asdepositing into molds. The hard candy portion contains one or moresugars selected from the group consisting of isomalt, sucrose, dextrose,corn syrup, lactitol, and lycasin. In one embodiment, the hard candyportion contains at least 50% (such as at least 75%, such as at least90%) by weight of such sugar(s).

In one embodiment, the outer edible form contains a pharmaceuticallyactive agent and the inner tablet contains a second portion of the samepharmaceutically active agent that is in the outer edible form. In oneembodiment, the outer edible form contains a pharmaceutically activeagent and the inner tablet contains a different pharmaceutically activeagent than that in the outer edible form. In one embodiment, the outeredible form disintegrates at a rate of at least 10 times, such as atleast 20 times, the rate of the inner tablet. The first and secondportions can be the same or different.

In one embodiment, the tablet having an outer edible form and an innertablet is coated with an immediate release sugar coating or filmcoating. In one embodiment, to produce such a tablet, the step followingthe fusing (heating) and subsequent cooling of the tablet would involvefurther sugar or film coating in a coating pan.

Hardness/Density of Tablet Shape/Tablet

In one embodiment, the tablet is prepared such that the tablet isrelatively soft (e.g., capable of disintegrating in the mouth or beingchewed). In one embodiment, the hardness of the tablet is preferablyless than about 3 kiloponds per square centimeter (kp/cm²) (e.g., lessthan about 2 kp/cm², such as less than about 1 kp/cm²).

Hardness is a term used in the art to describe the diametral breakingstrength as measured by conventional pharmaceutical hardness testingequipment, such as a Schleuniger Hardness Tester. In order to comparevalues across different size tablets, the breaking strength must benormalized for the area of the break. This normalized value, expressedin kp/cm², is sometimes referred in the art as tablet tensile strength.A general discussion of tablet hardness testing is found in Leiberman etal., Pharmaceutical Dosage Forms—Tablets, Volume 2, 2.sup.nd ed., MarcelDekker Inc., 1990, pp. 213-217, 327-329.

A more preferred test for hardness of the tablet of the presentinvention relies upon a Texture Analyzer TA-XT2i that is fitted with a 7millimeter diameter flat faced probe and setup to measure and reportcompression force in grams. The probe moves at 0.05 millimeters persecond to a depth of penetration of 2 millimeters. The maximumcompression force is recorded. In one embodiment, the measured forcesrecorded for tablets made in accordance with the present invention areless than 10,000 grams (e.g., less than about 1000 grams, such as lessthan about 700 grams. In one embodiment, the measured forces recordedfor tablets made in accordance with the present invention ranges fromabout 100 grams to about 6000 grams, such as from about 100 grams toabout 1000 grams, such as from about 75 grams to about 700 grams) with adeviation of ±50 grams. In another embodiment the measured forcesrecorded for tablets is less than 700 grams.

In one embodiment, the density of the tablet is less than about 2 g/cc(e.g., less than about 0.9 g/cc, such as less than about 0.8 g/cc, suchas less than about 0.7 g/cc). In one embodiment, the difference in thedensity of the powdered material following the compaction step is lessthan about 40 percent (e.g., less than about 25 percent, such as lessthan about 15 percent).

In one embodiment the tablet is a multilayer tablet. In one version ofthis embodiment, wherein the tablet is a bilayer tablet, the density ofone layer is at least 25% greater than the density of the other layer.In another embodiment, wherein the tablet is a bilayer tablet, thedensity of each individual layer less than 2 g/cc (e.g., less than about0.9 g/cc, such as less than about 0.8 g/cc, such as less than about 0.7g/cc). In another version of this embodiment, wherein the tablet is abilayer tablet, the density of the entire tablet less than 2 g/cc (e.g.,less than about 0.9 g/cc, such as less than about 0.8 g/cc, such as lessthan about 0.7 g/cc).

Tablets Coatings

In one embodiment, the tablet includes an additional outer coating(e.g., a translucent coating such as a clear coating) to help limit thefriability of the tablet. Suitable materials for translucent coatingsinclude, but are not limited to, hypromellose, hydroxypropylcellulose,starch, polyvinyl alcohol, polyethylene glycol, polyvinylalcohol andpolyethylene glycol mixtures and copolymers, and mixtures thereof.Tablets of the present invention may include a coating from about 0.05to about 10 percent, or about 0.1 to about 3 percent by weight of thetotal tablet.

Surface Treating of the Tablet

In one embodiment, the surface of the tablet shape and/or the tablet isfurther treated with energy (e.g., convection, infrared, or RF energy)to soften or melt the material on the surface of the tablet and thencooled or allowed to cool to further smooth the texture, enhance thegloss of surface of the tablet, limit the friability of the tablet,and/or provide a mark for identification. In one embodiment, the surfaceof the tablet is further exposed to infrared energy wherein the majority(at least 50 percent, such as least 90 percent, such as at least 99percent) of the wavelength of such infrared energy is from about 0.5 toabout 5 micrometers such as from about 0.8 to about 3.5 micrometers(e.g., by use of a wavelength filter). In one embodiment, the infraredenergy source is a quartz lamp with a parabolic reflector (e.g., tointensify the energy) and a filter to remove unwanted frequencies.Examples of such infrared energy sources include the SPOT IR 4150(commercially available from Research, Inc., Eden Prairie, Minn.).

Use of Tablet

The tablets may be used as swallowable, chewable, or orallydisintegrating tablets to administer the pharmaceutically active agent.

In one embodiment, the present invention features a method of treatingan ailment, the method including orally administering theabove-described tablet wherein the tablet includes an amount of thepharmaceutically active agent effective to treat the ailment. Examplesof such ailments include, but are not limited to, pain (such asheadaches, migraines, sore throat, cramps, back aches and muscle aches),fever, inflammation, upper respiratory disorders (such as cough andcongestion), infections (such as bacterial and viral infections),depression, diabetes, obesity, cardiovascular disorders (such as highcholesterol, triglycerides, and blood pressure), gastrointestinaldisorders (such as nausea, diarrhea, irritable bowel syndrome and gas),sleep disorders, osteoporosis, and nicotine dependence.

In one embodiment, the method is for the treatment of an upperrespiratory disorder, wherein the pharmaceutically active agent isselected from the group of phenylephrine, cetirizine, loratadine,fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine,chlophedianol, and pseudoephedrine.

In this embodiment, the “unit dose” is typically accompanied by dosingdirections, which instruct the patient to take an amount of thepharmaceutically active agent that may be a multiple of the unit dosedepending on, e.g., the age or weight of the patient. Typically the unitdose volume will contain an amount of pharmaceutically active agent thatis therapeutically effective for the smallest patient. For example,suitable unit dose volumes may include one tablet.

EXAMPLES

Specific embodiments of the present invention are illustrated by way ofthe following examples. This invention is not confined to the specificlimitations set forth in these examples.

Example 1 Manufacture of Powder Blend Containing Loratadine

The loratadine powder blend for an orally disintegrating tablet,containing the ingredients of Table 1, is manufactured as follows:

TABLE 1 Loratadine Powder Blend Formulation Ingredient G/Batch Mg/TabletDextrose Monohydrate 45.18 120.0 Loratadine 3.765 10.0 PolyethyleneGlycol 4000¹ 24.475 65.0 Maltodextrin² 15.062 40.0 Red Colorant 0.0280.075 Simethicone DC100³ 5.648 15.0 Sucralose USP 1.13 3.0 PolyethyleneOxide 1.883 5.0 Mint Flavor 2.824 7.5 Total 100 265.575 ¹Commerciallyavailable from Clariant PF in Rothausstr, Switzerland ²Commerciallyavailable from National Starch in Bridgewater, NJ ³Commerciallyavailable from SPI Pharma in Wilmington, DE

First, the sucralose, colorant, and flavor were placed together into a500 cc sealable plastic bottle. The mixture was then blendedend-over-end manually for approximately 2 minutes. The resultingmixture, the dextrose monohydrate, loratadine, and the polyethyleneoxide were then added to another 500 cc sealable plastic bottle andmixed end-over-end manually for approximately 5 minutes. The resultingmixture was then added to a planetary bowl mixer, and the simethiconeDC100 was added and mixed for approximately 3 minutes. Lastly, thepolyethylene glycol 4000 and the maltodextrin were added to the mixtureand mixed for approximately 3 minutes.

Example 2 Manufacture of Orally Disintegrating Tablet ContainingLoratadine

A portion of the powder blend from Example 1 was placed into a ½ inchdiameter forming cavity of an electrically insulative Teflon die platen.The powder blend was then tamped between an upper and lower flat-facedmetal forming tools into a shape conformal to the surface of the formingtools. The tamping pressure was typically between 10 and approximately50 psi of pressure. The forming tools, die platen and tablet shape werethen placed between the upper RF electrode and lower RF electrodepowered by an RF heating unit using a COSMOS Model C10X16G4 (CosmosElectronic Machine Corporation, Farmingdale, N.Y.) RF generator havingan output of 4 KW of power, frequency of 27 MHz, and the vacuumcapacitor is set at 140. The forming tools are heated with reciculatingwater at a temperature of 57° C. The upper RF electrode was brought intocontact with the upper forming tool and the lower RF electrode isbrought into contact with lower forming tool. The RF heating unit wasenergized for 2 to 5 seconds. The resulting tablet was then ejected fromthe die platen using the lower forming tool.

Example 3 Manufacture of Orally Disintegrating Tablet ContainingDiphenhydramine

The diphenhydramine powder blend for an orally disintegrating tablet,containing the ingredients of Table 2, was manufactured as follows. Thesucralose, yellow colorant, flavors, polyethylene glycol andmaltodextrin from the formula in Table 2 were passed through a 20 meshscreen. The sieved materials were placed into a 500 cc plastic bottleand blended end over end with the remaining materials in Table 2. Thepowder blend was placed into the forming cavity, tamped, and activatedwith RF energy as described in Example 2 for approximately 2 to 5seconds to form the orally disintegrating tablet and subsequentlyremoved from the die platen.

TABLE 2 Powder Blend Formulation Containing Diphenhydramine (DPH)Ingredient G/Batch Mg/Tablet Dextrose Monohydrate 304.11 219.0Diphenhydramine (Coated)³ 49.57 35.70 Polyethylene Glycol 8000¹ 44.1631.80 Maltodextrin² 88.46 63.70 Yellow Colorant 0.78 0.56 Orange Flavor1.65 1.19 Vanilla Flavor 2.21 1.59 Sucralose USP 1.11 0.80 Citric AcidUSP Anhydrous 7.96 5.73 Total 500.00 360.07 ¹Commercially available fromClariant PF in Rothausstr, Switzerland ²Commercially available fromNational Starch in Bridgewater, NJ ³Encapsulated Diphenhydramine coatedutilizing cellulose acetate and polymethacrylate, utilizing processoutlined in U.S. Pat. No. 5,997,905 incorporated herein by reference

Example 4 Manufacture of Orally Disintegrating Tablet Placebo ContainingDextrose Monohydrate

The placebo powder blend for an orally disintegrating tablet, containingthe ingredients of Table 3, was manufactured as follows. The sucralose,yellow colorant, flavors, polyethylene glycol and maltodextrin from theformula in Table 3 were passed through a 20 mesh screen. The sievedmaterials were placed into a 500 cc plastic bottle and blended end overend with the remaining materials in Table 3. The powder blend was placedinto the forming cavity, tamped, and activated with RF energy asdescribed in Example 2 for approximately 2 to 5 seconds to form theorally disintegrating tablet and subsequently removed from the dieplaten.

TABLE 3 Powder Blend Formulation Ingredient G/Batch Mg/Tablet DextroseMonohydrate 283.04 255.0 Polyethylene Glycol 8000¹ 35.30 31.80Maltodextrin² 70.71 63.70 Yellow Colorant 0.62 0.56 Orange Flavor 1.321.19 Vanilla Flavor 1.76 1.59 Sucralose USP 0.89 0.80 Citric AcidAnhydrous USP 6.36 5.73 Total 400.00 360.37 ¹Commercially available fromClariant PF in Rothausstr, Switzerland ³Commercially available fromNational Starch in Bridgewater, NJ

Example 5 Manufacture of Orally Disintegrating Tablet Placebo ContainingErythritol

The placebo powder blend for an orally disintegrating tablet, containingthe ingredients of Table 4, was manufactured as follows. The sucralose,yellow colorant, flavors, polyethylene glycol and maltodextrin from theformula in Table 4 were passed through a 20 mesh screen. The sievedmaterials were placed into a 500 cc plastic bottle and blended end overend with the remaining materials in Table 4. The powder blend was placedinto the forming cavity, tamped, and activated with RF energy asdescribed in Example 2 for approximately 2 to 5 seconds to form theorally disintegrating tablet and subsequently removed from the dieplaten.

TABLE 4 Placebo Powder Blend Formulation Containing ErythritolIngredient G/Batch Mg/Tablet Erythritol Directly 212.28 255.0Compressible³ Polyethylene Glycol 8000¹ 26.47 31.80 Maltodextrin² 53.0363.70 Yellow Colorant 0.47 0.56 Orange Flavor 0.99 1.19 Vanilla Flavor1.32 1.59 Sucralose USP 0.67 0.80 Citric Acid Anhydrous USP 4.77 5.73Total 300.00 360.37 ¹Commercially available from Clariant PF inRothausstr, Switzerland ³Commercially available from National Starch inBridgewater, NJ ⁴Commercially available from Corn Products inWestchester, IL

Example 6 Manufacture of a Comparative Compressed Chewable PlaceboTablet

The placebo powder blend for a comparative chewable placebo tablet,containing the ingredients of Table 5, was manufactured as follows. Thesucralose, yellow color, and flavors were passed through a 20 meshscreen prior to blending. The sieved materials were blended with theremaining materials in the formula in Table 5 and added to a 500 ccplastic bottle and blended end over end for approximately 3 minutes anddischarged. The tablets were compressed using two different compressionforces as follows: Tablets (a) were compressed on a single stationmanual Carver press (commercially available from Carver PressCorporation in Wabash, Ind.) at 0.7 Metric tons (6.86 KiloNewtons) andTablets (b) were compressed at 0.25 Metric tons (2.45 KiloNewtons).Tablets (b) were extremely friable and fragile given the low amount ofpressure applied to the formulation.

TABLE 5 Placebo Powder Blend Formulation for Compressed TabletIngredient G/Batch Mg/Tablet Dextrose Monohydrate 114.773 138.00Polyethylene Glycol 4000¹ 41.584 50.00 Maltodextrin² 35.763 43.00 BlueColorant 0.075 0.0907 Yellow Colorant 0.153 0.1842 Vanilla Flavor 1.8302.20 Sucralose USP 1.248 1.50 Mint Flavor¹ 4.574 5.50 Total 200 240.47¹Commercially available from Clariant PF in Rothausstr, Switzerland³Commercially available from National Starch in Bridgewater, NJ

Example 7 Manufacture of a Comparative Compressed Chewable ContainingAcetaminophen

The placebo powder blend for a chewable tablet, containing theingredients of Table 6, was manufactured as follows. The sucralose,yellow color, flavors, and citric acid were passed through a 20 meshscreen prior to blending. The sieved materials were blended with theremaining materials in the formula in Table 6 and added to a 500 ccplastic bottle and blended end over end for approximately 3 minutes anddischarged. The tablets were compressed using two different compressionforces as follows: Tablets (a) were lightly compressed on a singlestation manual Carver press at 0.7 Metric tons (6.86 KiloNewtons) andTablets (b) were compressed at 0.25 Metric tons (2.45 KiloNewtons).Tablets (b) were extremely friable and fragile given the low amount ofpressure applied to the formulation.

TABLE 6 Powder Blend Formulation Containing Acetaminophen IngredientG/Batch Mg/Tablet Dextrose Monohydrate 32.284 94.00 Acetaminophen(Coated)³ 29.989 87.32 Polyethylene Glycol 4000¹ 5.152 15.00Maltodextrin² 20.607 60.00 Yellow Colorant 0.120 0.35 Orange Flavor0.343 1.00 Vanilla Flavor 0.515 1.50 Sucralose USP 0.343 1.00Crosslinked Povidone⁵ 2.061 6.00 Polyethylene Oxide (Grade 6.869 20.00WSR 303)⁴ Citric Acid USP Anhydrous 1.717 5.00 Total 100 291.17¹Commercially available from Clariant PF in Rothausstr, Switzerland²Commercially available from National Starch in Bridgewater, NJ³Encapsulated Acetaminophen coated utilizing cellulose acetate andpovidone, utilizing process outlined in U.S. Pat. No. 4,851,226incorporated herein by reference ⁴Commercially available from the DOWCorporation in Midland, MI ⁵Commercially available as Kollidon CL-M fromthe BASF Corporation in Florham Park, NJ

Example 8 Density Measurements of ODT and Compressed Tablets

Three tablets from each of Examples 3, 4, 5, 6, and 7 and a comparativeorally disintegrative tablet (Alavert® Loratidine Orally DisintegratingTablet, Wyeth Consumer Healthcare, Madison, N.J., USA) were measured todetermine the density of compressed tablets and tablets producedutilizing the method of the present invention. The density wascalculated utilizing the volume of a cylinder as calculated using thewidth and thickness of the tablet divided by the weight of individualtablets.

TABLE 8 Tablet Density Measurements Weight Diameter Height VolumeDensity Example (mg) (mm) (mm) (mm³) (mg/mm³) Example 3 (1) 379 13.135.00 677.0 0.560 Example 3 (2) 403 13.10 4.97 669.9 0.602 Example 3 (3)409 13.03 4.87 649.4 0.630 Example 4 (1) 347 12.90 4.85 633.9 0.547Example 4 (2) 416 12.97 4.96 655.3 0.635 Example 4 (3) 398 13.06 4.95663.1 0.600 Example 5 (1) 419 12.90 5.38 703.2 0.596 Example 5 (2) 39713.15 5.32 722.5 0.549 Example 5 (3) 352 12.87 5.00 650.5 0.541 Example6a (1) 399 11.18 3.32 325.9 1.220 Example 6a (2) 372 11.16 3.06 299.31.240 Example 6a (3) 391 11.18 3.25 319.0 1.230 Example 6b (1) 433 11.204.27 420.7 1.030 Example 6b (2) 442 11.22 4.35 430.1 1.030 Example 6b(3) 404 11.18 3.93 385.8 1.050 Example 7a (1) 364 11.20 3.26 321.2 1.130Example 7a (2) 328 11.18 2.94 288.6 1.140 Example 7a (3) 404 11.17 3.65357.7 1.130 Example 7b (1) 413 11.25 4.66 463.2 0.890 Example 7b (2) 45111.21 5.00 493.5 0.910 Example 7b (3) 437 11.22 4.82 476.6 0.920Alavert ®¹ Tablet 1 305.67 9.68 3.67 270.0 1.13* Alavert ®¹ Tablet 2296.50 9.71 3.65 270.0 1.10* Alavert ®¹ Tablet 3 294.81 9.71 3.63 269.01.10* *The Alavert tablets have beveled edges which slightly lowered thevolume. Therefore, Alavert ® Loratidine Orally Disintegrating Tabletswere also measured for density using a volume displacement method,wherein the tablets were placed into a volume of mineral oil. Thedensity for 3 tablets of Alavert were measured at 1.6, 1.2, and 1.5mg/mm³ using this method.As is shown in table 8, the ODT tablets of the present invention(Examples 3, 4, and 5) has densities ranging from 0.541-0.635 mg/mm³,which were much lower than the comparative chewable tablets of Examples6 and 7 (having densities ranging from 0.890 1.240 mg/mm³) and theAlavert® orally disintegrating tablets (having densities ranging from1.10-1.6 mg/mm³). Thus, the ODT tablets of the present invention, thus,had densities approximately half of that of the comparative examples.

Example 9 Disintegration Test Utilizing Texture Analyzer TA XT Plus

The following test was performed utilizing the Texture Analyzer TA XTPlus, commercially available from Texture Technologies in Scarsdale,N.Y. The texture Analyzer was equipped with a TA-55 probe, and set to aprobe speed of 0.1 mm/sec. The individual tablet was placed into a 5 mmgraduated cylinder, and placed onto the short axis. 20 grams of forcewas applied to the tablet via the 5 mm probe. The force was applied andat approx. 10 mL of de-ionized water at 25° C. was added to cover thetablet. The force was analyzed over time and the following tablets wereanalyzed: the tablets of Example 6a and the tablets of Example 3. Thetablets of the present invention (Example 3) disintegrated immediatelyfollowing the addition of the water as indicated by the probe distance,which increased from 0 mm to greater than 1 mm between 10 and 20seconds. The tablets from Example 6a, which were representative ofchewable tablets, disintegrated in 84.30 seconds from the addition ofwater as measured by the change in slope in the texture analyzer, wheretablets of Example 3 were completely disintegrated in 6.99 seconds fromthe addition of water.

Example 10 Preparation of Tablet Cores and Sintered Tablet ContainingAcetaminophen

The tablet cores of Table 9 are prepared as follows. Equal parts ofsucralose, tartaric acid, strawberry flavor, maltodextrin and Sorbidex Ppowdered sobirtol are manually passed through a 50 mesh screen. Theloratidine, flavor blend, Sorbidex P and Tapioca Maltodextrin are addedto the above mixture in a plastic bottle, mixed end-over end forapproximately three minutes, and then discharged. The blend is thenindividually dosed into a tablet die utilizing 624 mg of the blend pertablet

A portion of the powder blend from Example 1 is placed into anelectrically insulative Teflon, or ceramic die block, approximately 1.1″in diameter and 0.175″ thick. The powder blend is then tamped between anupper and lower metal forming tools into a shape conformal to thesurface of the forming tools. The tamping pressure is typically between10 and approximately 100 psi of pressure. The forming tools, die blockand tablet shape are then placed between the upper electrode and lowerelectrode of an RF heating unit The upper electrode is brought intocontact with the upper forming tool and the lower electrode is broughtinto contact with lower forming tool. The RF heating unit is energizedfor 2 seconds. After cooling, the resulting tablet dosage form is thenejected from the die block using the lower forming tool.

TABLE 9 Loratidine 10 mg Dosage Form Core Formulation Material G/Batchmg/tab Weight % Dextrose Monohydrate, Fine powder 33.86 118.51 33.86Flavor Blend² 5.88 20.58 5.88 Sorbidex P¹ (Sorbitol powder) 33.86 118.5133.86 Loratidine 2.86 10.0 2.86 Tapioca Maltodextrin (N-Zorbit M³) 23.5382.36 23.53 TOTAL 100.0 350.0 100.0 ¹Commercially available from CargillCorporation in Wayzata, Minnesota ²Contains equal parts of StrawberryCream Flavor, Sucralose, Tartaric Acid, Maltodextrin, Sorbidex P(Sorbitol powder) ³Commercially available from National Starch inBridgewater, NJ

Example 11 Preparation of Bi-Layer Orally Disintegrating Tablet

A bi-layered orally disintegrating tablet having loratadine in one layerand diphenhydramine in the other layer is manufactured as follows.265.58 mg of the powder blend containing loratadine from Table 1 isplaced into the forming cavity and tamped. 360.073 mg of the powderblend containing diphenhydramine from Table 2 is then added into theforming cavity and tamped to create a 625.65 mg tablet. The cavity isthen activated with RF energy as described in Example 2 forapproximately 2 to 5 seconds to form the orally disintegrating tabletand subsequently removed from the die platen.

Example 12 Preparation of Bi-Layer Placebo Orally Disintegrating Tablet(ODT)

A bi-layered orally disintegrating placebo tablet having colorant in onelayer and no colorant in the other layer is manufactured as follows.90.0 mg of the powder blend containing colorant from Table 10 is placedinto the forming cavity and lightly tamped. 90.0 mg of the powder blendwithout colorant from Table 11 is then added into the forming cavity andtamped. The cavity is then activated with RF energy as described inExample 2 for approximately 2 to 5 seconds to form the orallydisintegrating tablet at 180.0 mg and subsequently removed from the dieplaten.

TABLE 10 Layer 1 of Bilayer Placebo ODT Material G/Batch mg/tab layerWeight % Dextrose Monohydrate, Fine powder 57.020 51.318 57.020Sucralose 0.473 0.426 0.473 Peppermint Flavor¹ 2.100 1.890 2.100 VanillaFlavor¹ 0.900 0.810 0.900 Propylene Glycol 4000 20.883 18.795 20.883Tapioca Maltodextrin (N-Zorbit M²) 18.444 16.600 18.444 Blue #1 Al LakeColorant 0.060 0.0540 0.060 Yellow #10 Al Lake Colorant 0.120 0.1080.120 TOTAL 100.0 90.00 100.0 ¹Commercially available from theInternational Flavors and Fragrances Corporation in Hazlet, NJ²Commercially available from National Starch in Bridgewater, NJ

TABLE 11 Layer 2 of Bilayer Placebo ODT Material G/Batch mg/tab layerWeight % Dextrose Monohydrate, Fine powder 57.123 51.411 57.123Sucralose 0.474 0.427 0.474 Peppermint Flavor 2.100 1.890 2.100 VanillaFlavor 0.900 0.810 0.900 Propylene Glycol 4000 20.921 18.829 20.921Tapioca Maltodextrin (N-Zorbit M) 18.482 16.634 18.482 TOTAL 100.0 90.0100.0

It is understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the claims.

What is claimed is:
 1. A process for making a tablet comprising a firstlayer and a second layer, said method comprising: adding a first powderblend to a die platen, wherein said first powder blend comprises apharmaceutically active agent and a binder; adding a second powder blendto said die platen, wherein said second powder blend comprises a binderand wherein the composition of said second powder blend is differentfrom the composition of said first powder blend; tamping said firstpowder blend and second powder blend in said die platen to form a tampedtablet shape; and applying energy to said tamped tablet shape for asufficient period of time to activate said binders within said tabletshape to fuse said tablet shape into said tablet such that said tablethas a density less than about 0.8 g/cc and said tablet disintegrates inthe mouth when placed on the tongue in less than about 30 seconds. 2.The process of claim 1, wherein said binder within said first powderblend and said binder within said second powder blend are meltablematerials having a melting point of from about 30° C. to about 140° C.and said tablet shape is exposed to said energy for a sufficient periodof time to melt or soften said binders.
 3. The process of claim 1,wherein said binder within said first powder blend is a RF-meltablebinder, and said tablet shape is exposed to RF energy for a sufficientperiod of time to melt or soften said RF-meltable binder.
 4. The processof claim 1, wherein said first powder blend comprises a RF-heatablematerial, and said tablet shape is exposed to RF energy for a sufficientperiod of time to heat said RF-heatable material such that saidRF-heatable material melts or softens said binder within said firstpowder blend.
 5. The process of claim 1, wherein said binder within saidfirst powder blend and said binder within said second powder blend arewater-activating binding materials, said first powder blend and saidsecond powder blend further comprise water-containing materials, andsaid tablet shape is exposed to said energy for a sufficient period oftime to heat the water-containing materials above their dehydrationtemperature.
 6. The process of claim 1, wherein said first powder blendcomprises particles comprising said first pharmaceutically active agentwherein said particles are coated with said binder.
 7. The process ofclaim 1, wherein said process further comprises tamping said firstpowder blend prior to adding said second powder blend to said dieplaten.
 8. The process of claim 1, wherein the surface of said tablet isfurther exposed to infrared energy wherein the majority of thewavelength of said infrared energy from about 0.5 to about 5micrometers.
 9. The process of claim 1 wherein said tamping stepcomprises tamping at a pressure of less than about 1000 pounds persquare inch.
 10. The process of claim 1 wherein said tamping of saidfirst powder blend is done at a pressure of less than about 1000 poundsper square inch prior to adding said second powder blend.